For the preparation of APIs it is absolutely necessary to use isomerically pure building blocks and/or highly stereoselective procedures because by-products in APIs may have adverse effects in the treatment of illnesses. Therefore, a high purity is requested for all APIs.
Enantiomerically pure (S)-1,1,1,-trifluoro-2-propanol is an important building block for the preparation of isomerically pure active pharmaceutical ingredients (APIs), used for the treatment of neurological and neuropsychiatric disorders.
As neither the enantiomeric purity of the building block (S)-1,1,1-trifluoro-2-propanol nor that of its subsequent intermediates in the syntheses of the respective APIs can be enriched, e.g. by crystallization, it is paramount to use (S)-1,1,1-trifluoro-2-propanol of high enantiomerical purity in the synthesis of such APIs.
J. W. C. Crawford (J. Chem. Soc. 1967, 2332) described a method for producing (S)-1,1,1-trifluoro-2-propanol, where (rac)-1-(trifluoromethylethoxy)propionic acid (the adduct of the alcohol and acrylic acid) was separated into its optical isomers through its quinine salt, and pure (S)-1,1,1-trifluoro-2-propanol was obtained from the enantiomeric pure alkoxy-acid by alkaline hydrolysis and distillation. Although this method affords (S)-1,1,1-trifluoro-2-propanol of high enantiomeric purity (optical rotation: −5.6°), the method is not suitable for large scale production.
T. C. Rosen et al. (Chimica Oggi Suppl. 2004, 43) prepared both (R)- and (S)-1,1,1-trifluoro-2-propanol by asymmetric reduction of 1,1,1-trifluoroacetone using alcohol dehydrogenases (ADHs) either in their natural hosts or as recombinant enzymes expressed in E. coli. Resting whole cells or crude cell free extracts may be used and in the latter case addition of a cofactor regenerating system is necessary.
M. Buccierelli et al. (Synthesis 1983, 11, 897) describe the preparation of (S)-1,1,1-trifluoro-2-propanol by reduction of 1,1,1-trifluoroacetone using (resting) Baker's yeast on lab scale. Although the reaction proceeds fast (4 h), a 300 times excess of yeast with respect to substrate is required, the substrate concentration is only 2.5 g/kg yeast suspension, and (S)-1,1,1-trifluoro-2-propanol is obtained only with approx. 80% ee (as calculated from the optical rotation of −4.5° for the isolated alcohol, compared with −5.6° for the pure alcohol), a value which is far too low for our needs. In addition, the isolation protocol, based on repeated solvent extraction in combination with distillation, is not applicable economically on large scale.
Asymmetric hydrogenations of trifluoromethyl (aryl or alkyl) ketones using rhodium catalysts of type [Rh((S)-Cy, Cy-oxoProNOP)(OCOCF3)]2 in toluene with up to 98% ee have been reported by A. Kuroki (Org. Lett. 2001, 3, 457).
Analogue ruthenium catalysts to types 3 and 4 described herein, but containing BINAP instead of MeOBIPHEP as chiral ligands have been applied in the asymmetric hydrogenation of aryl alkyl ketones (mainly acetophenone and derivatives) with up to 99% ee (R. Noyori et al., J. Am. Chem. Soc. 1995, 117, 2675; Angew. Chem. 2001, 113, 40; J. Am. Chem. Soc. 2002, 124, 6508 and J. Am. Chem. Soc. 2003, 125, 13490).
Noyori also reported lately with these Ru-BINAP-catalysts (J. Am. Chem. Soc. 2005, 127, 8288) the successful asymmetric hydrogenation of tert.-butyl (alkyl, aryl or alkenyl) ketones. It is reported that catalysts of type 3 always require strong bases (such as alcoholates) as activators (R. Noyori et al., J. Am. Chem. Soc. 2003, 125, 13490).
In addition, Noyori described (J. Am. Chem. Soc. 2003, 125, 13490) as well that the presence of an alcoholic solvent, such as 2-propanol, ethanol or methanol, is mandatory for optimum reactivity.